Similar links found with amphetamine and opioid abuse

Action Points

Cannabis use disorders were associated with risk of conversion from schizotypal disorder to overt schizophrenia in a prospective, longitudinal Danish cohort study, with a conversion rate exceeding previous estimates.

Understand that the etiology of disease conversion in people with schizotypal disorder is complex, and conversion rates are generally high even in the absence of a history of substance abuse.

Cannabis use disorders were associated with risk of conversion from schizotypal disorder to overt schizophrenia in a prospective, longitudinal cohort study.

In a population-based sample of individuals with incident schizotypal disorder the conversion rate after 20 years was 33.1% (95% CI 29.3%-37.3%) overall, and 58.2% (95% CI 44.8%-72.2%) among participants identified with cannabis use disorders, wrote Carsten Hjorthoj, PhD, MSc, of University Hospital, Mental Health Center Copenhagen, Hellerup, Denmark, and colleagues.

That level of conversion exceeds previous estimates of 25%-50% within 5 years after diagnosis of schizotypal disorder, the researchers noted in JAMA Psychiatry.

Hjorthoj and colleagues also examined amphetamine and opioid misuse, which had stronger associations with conversion than did cannabis use:

Cannabis: HR 1.30 (95% CI 1.01-1.68)

Amphetamine use disorders: HR 1.90 (95% CI 1.14-3.17)

Opioid use disorders: HR 2.74 (95% CI 1.38-5.45)

Understanding the etiology of the disease conversion in people with schizotypal disorder is a complex task, the researchers indicated. Conversion rates are generally high even in the absence of a history of substance abuse.

Previous studies have linked substance misuse and cannabis in particular to schizotypal disorder and schizophrenia. One found a five-fold risk for development of schizophrenia associated with cannabis use in otherwise healthy individuals. "Cannabis use has been extensively studied as a risk factor for schizophrenia in the general population, and our study revealed this association," Hjorthoj and colleagues wrote.

Data on 2,539 individuals diagnosed with schizotypal disorder, identified from the nationwide Danish registries of all persons born in Denmark from January 1, 1981, to August 10, 2014, were included in the analysis. Just over half were men and the mean age was 21.

Although substance abuse disorders demonstrated an association for conversion, predisposition due to parental schizophrenia and other types of parental mental illness was not found. This was surprising given that "parental history of schizophrenia is a well-known risk factor for schizophrenia in the offspring and parental severe mental illness is associated with substance use in the offspring." The authors described this as a "ceiling effect," although noted that the reasons for this "lack of association are not clear."

In Denmark a high proportion of patients are prescribed antipsychotic medications "which raises the concern that some of these patients with schizotypal disorder might already have met the threshold for a psychotic disorder such as schizophrenia before the eventual diagnosis of schizophrenia," study authors wrote.

To explore the impact of this as a confounder, the study authors conducted a sensitivity analysis, during which they censored individuals at the time when they received their first antipsychotic prescription. This censoring "had little effect on the estimated associations" suggesting that antipsychotic prescriptions are not a "causal risk factor for conversion," but instead "may be a marker of already increased risk."

Study limitations included an inability to validate the diagnosis of schizotypal disorder due to prescribing patterns of antipsychotic medications in Denmark. The high prevalence of these prescriptions "might indicate that not all of [the study participants] had true schizotypal disorder but may have in fact have had misdiagnosed schizophrenia from the start."

Relying on registries for those being treated for substance use disorders may have led to conservative estimates of the extent of the conversion via illicit substance use risk.

Lastly, analysis could not be adjusted to account for all variables, such as tobacco use, which often coincides with cannabis use and for which "some evidence" exists for the development of psychosis, they wrote.

In conclusion, study authors wrote that, "Preventing or treating substance use disorders, especially cannabis and amphetamine use disorders, may have some efficacy in reducing the additional risk attributable to substance use disorders" in conversion from schizotypal disorder to schizophrenia, "indicating a need for universal and substance-targeted prevention in individuals with schizotypal disorder."

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